Rubinstein-Taybi syndrome (RTS) is a rare childhood neurodevelopmental disease (NDD) caused by genetic mutations in CREBBP (~70%) or EP300 (~8%) genes. Children with RTS show intellectual disability and other cognitive deficits. Being an NDD, historically it has been very difficult to study in vitro. To address this problem, we generated induced Pluripotent stem cells (iPSCs) from skin sample obtained from RTS patients. Using the iPSCs, we have generated in vitro RTS disease models and showed that patient iPSCs recapitulate NDD associated neuronal defects such as sub-optimal differentiation and migration. As mutations in the CREBBP gene impacts histone acetylation, we hypothesised that FDA approved Histone Deacetylase inhibitors (HDACi) can be used to attenuate the neural deficits in RTS, paving a way for the development of a treatment for affected children. We used one such FDA approved HDACi drug and showed restoration of the neuron-differentiation potential of RTS patient derived iPSCs. We then used patient iPSCs to generate cerebral, cortical and diencephalic organoids and found impaired neurogenesis and organoid cytoarchitecture. Importantly, the patient's cerebral organoids showed microcephaly, a key trait found in RTS patients. As the human brain is extremely plastic in the first years of life, we presume that any intervention that may improve the cognitive functions of the brain, could impart significant benefits to the RTS children. While HDACi have the potential to be “repurposed” towards RTS, long term toxicity still remains a concern. Hence, we further developed a novel antisense oligonucleotide (ASO) approach to bypass the mutated, but dispensable, exon of the CREBBP gene in an attempt to restore the loss of protein dosage and/or function due RTS mutations. Given the rapid translation potential of ASOs, our proof-of-concept study might help faster development of potential treatment for some RTS patients.